About 2% of the world population (123 million individuals) are chronically infected with the hepatitis C virus (HCV). Chronic infection puts these individuals at risk for the development of hepatitis, cirrhosis, liver failure and hepatocellular carcinoma making chronic hepatitis C the leading cause for liver transplantation worldwide. In the United States a seroprevalence rate of 1.8% has been reported and HCV is associated with more than half of an increasing number of newly diagnosed hepatocellular carcinomas.
Current therapy combining pegylated interferon-alpha with ribavirin achieves cure rates of just above 50% (Fried et al., 2002, N Engl J Med 347:975-82; Manns et al., 2001, Lancet 358:958-965). Several difficult to treat patient groups show decreased response rates or cannot tolerate therapy at all. These include patients that have failed to respond to standard therapy, African Americans, patients with HIV-coinfection or end-stage liver disease and patients after liver transplantation. Currently, HCV infection of the graft after liver transplantation is universal, usually leading to rapid fibrosis progression and subsequent graft failure. This accounts for the poor outcome of liver transplantation for HCV-induced cirrhosis compared to other indications (Forman et al., 2002, Gastroenterology 122:889-96).
HCV is a member of the family Flaviviridae, which also includes Pestiviruses and Flaviviruses. The HCV virion consists of an enveloped nucleocapsid containing the viral genome, a single, positive stranded RNA of approximately 9,600 nucleotides. The HCV genome encodes a single long open reading frame giving rise to a viral polyprotein of over 3000 amino acids that then undergoes co- and post-translational proteolytic processing to generate the mature viral proteins: C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B. The viral structural proteins, including core, the capsid protein E1, and E2, are encoded by the first third of the polyprotein p7 (a putative ion channel) and nonstructural (NS) proteins, encoded by the C-terminal two-thirds of the polyprotein, are components of the HCV RNA replication complex. The replication of the viral genome occurs through a negative strand RNA intermediate.
HCV replication and the HCV non-structural proteins involved in this process have been identified as targets for development of antiviral compounds. Identification of antiviral compounds that inhibit the HCV non-structural proteins and replication of subgenomic HCV replicons have been disclosed (see, for example, U.S. Pat. No. 7,241,796). Compounds that bind NS4B and inhibit replication of subgenomic HCV replicons have also been reported (U.S. Patent Application Publication No. 20070269420). Nonetheless, there remains an urgent need for additional compounds, compositions, and methods that can be used to treat or prevent HCV infections.